A Combination of HA and PA Mutations Enhances Virulence in a Mouse-Adapted H6N6 Influenza A Virus

Tan, Likai; Su, Shuo; Smith, David K.; He, Shuilin; Zheng, Yun; Shao, Zhenwen; Ma, Jun; Zhu, Hua; Zhang, Guihong

doi:10.1128/jvi.01736-14

Cited by 38 publications

(22 citation statements)

References 46 publications

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“…The HPAI H5N8 virus caused severe clinical disease in mice but only at high-inoculation dosages2930. However, the H5N8 viruses used here demonstrated lethal pathogenicity within 5 dpi in 2 sequential passages at low-inoculation dosage, while generally, HPAI and LPAI viruses demonstrated detectably increased virulence after 5 or more passages in mice2450515253. The rapid acquisition of virulence by the H5N8 viruses implies increased pandemic potential, especially with worldwide spread and rapid evolution454.…”

Section: Discussionmentioning

confidence: 80%

Rapid acquisition of polymorphic virulence markers during adaptation of highly pathogenic avian influenza H5N8 virus in the mouse

Choi

Baek

Kwon

et al. 2017

Sci Rep

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Emergence of a highly pathogenic avian influenza (HPAI) H5N8 virus in Asia and its spread to Europe and North America has caused great concern for human health. Although the H5N8 virus has been only moderately pathogenic to mammalian hosts, virulence can still increase. We evaluated the pathogenic potential of several H5N8 strains via the mouse-adaptation method. Two H5N8 viruses were sequentially passaged in BALB/c mice and plaque-purified from lung samples. The viruses rapidly obtained high virulence (MLD50, up to 0.5 log10 PFU/mL) within 5 passages. Sequence analysis revealed the acquisition of several virulence markers, including the novel marker P708S in PB1 gene. Combinations of markers synergistically enhanced viral replication and polymerase activity in human cell lines and virulence and multiorgan dissemination in mice. These results suggest that H5N8 viruses can rapidly acquire virulence markers in mammalian hosts; thus, rapid spread as well as repeated viral introduction into the hosts may significantly increase the risk of human infection and elevate pandemic potential.

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Section: Discussionmentioning

confidence: 80%

Rapid acquisition of polymorphic virulence markers during adaptation of highly pathogenic avian influenza H5N8 virus in the mouse

Choi

Baek

Kwon

et al. 2017

Sci Rep

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“…Since MOV10 was among the vRNP complexassociated proteins and inhibited influenza virus replication, we hypothesized that MOV10 could affect the polymerase activity. To investigate this, we employed the dual-luciferase minigenome system in our study (37,51). The pPolI-Luci-T plasmid was constructed by inserting the coding sequence of firefly luciferase in a negative-sense orientation flanked with influenza virus cRNA promoter ends.…”

Section: Isolation Of Influenza a Virus Vrnp Complex And Identificatimentioning

confidence: 99%

“…The influenza A/PR/ 8/34 (H1N1) virus and A/Guangdong/1/2009 (H1N1) virus were rescued using an eight-plasmid-based reverse-genetics system (35)(36)(37). Plasmids of PB1, PB2, PA, NP, HA, NA, M, and NS on the pHW2000 vector were used for transfection.…”

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confidence: 99%

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Host Protein Moloney Leukemia Virus 10 (MOV10) Acts as a Restriction Factor of Influenza A Virus by Inhibiting the Nuclear Import of the Viral Nucleoprotein

Zhang

Huang

Tan

et al. 2016

J Virol

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The viral ribonucleoprotein (vRNP) complex of influenza A viruses (IAVs) contains an RNA-dependent RNA polymerase complex (RdRp) and nucleoprotein (NP) and is the functional unit for viral RNA transcription and replication. The vRNP complex is an important determinant of virus pathogenicity and host adaptation, implying that its function can be affected by host factors. In our study, we identified host protein Moloney leukemia virus 10 (MOV10) as an inhibitor of IAV replication, since depletion of MOV10 resulted in a significant increase in virus yield. MOV10 inhibited the polymerase activity in a minigenome system through RNA-mediated interaction with the NP subunit of vRNP complex. Importantly, we found that the interaction between MOV10 and NP prevented the binding of NP to importin-␣, resulting in the retention of NP in the cytoplasm. Both the binding of MOV10 to NP and its inhibitory effect on polymerase activity were independent of its helicase activity. These results suggest that MOV10 acts as an anti-influenza virus factor through specifically inhibiting the nuclear transportation of NP and subsequently inhibiting the function of the vRNP complex. IMPORTANCEThe interaction between the influenza virus vRNP complex and host factors is a major determinant of viral tropism and pathogenicity. Our study identified MOV10 as a novel host restriction factor for the influenza virus life cycle since it inhibited the viral growth rate. Conversely, importin-␣ has been shown as a determinant for influenza tropism and a positive regulator for viral polymerase activity in mammalian cells but not in avian cells. MOV10 disrupted the interaction between NP and importin-␣, suggesting that MOV10 could also be an important host factor for influenza virus transmission and pathogenicity. Importantly, as an interferon (IFN)-inducible protein, MOV10 exerted a novel mechanism for IFNs to inhibit the replication of influenza viruses. Furthermore, our study potentially provides a new drug design strategy, the use of molecules that mimic the antiviral mechanism of MOV10.

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“…Several reports have described the replication benefits resulted from a single amino acid mutation in one of the four polymerase complex proteins323334. Even though another study indicated no correlation between viral replication and polymerase activity35, there may be some contradictions between different virus subtypes and strains. We also examined whether the PA E31K mutation would increase viral polymerase complex activity.…”

Section: Discussionmentioning

confidence: 99%

Single PA mutation as a high yield determinant of avian influenza vaccines

Lee

Kim

Park

et al. 2017

Sci Rep

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Human infection with an avian influenza virus persists. To prepare for a potential outbreak of avian influenza, we constructed a candidate vaccine virus (CVV) containing hemagglutinin (HA) and neuraminidase (NA) genes of a H5N1 virus and evaluated its antigenic stability after serial passaging in embryonated chicken eggs. The passaged CVV harbored the four amino acid mutations (R136K in PB2; E31K in PA; A172T in HA; and R80Q in M2) without changing its antigenicity, compared with the parental CVV. Notably, the passaged CVV exhibited much greater replication property both in eggs and in Madin-Darby canine kidney and Vero cells. Of the four mutations, the PA E31K showed the greatest effect on the replication property of reverse genetically-rescued viruses. In a further luciferase reporter, mini-replicon assay, the PA mutation appeared to affect the replication property by increasing viral polymerase activity. When applied to different avian influenza CVVs (H7N9 and H9N2 subtypes), the PA E31K mutation resulted in the increases of viral replication in the Vero cell again. Taken all together, our results suggest the PA E31K mutation as a single, substantial growth determinant of avian influenza CVVs and for the establishment of a high-yield avian influenza vaccine backbone.

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A Combination of HA and PA Mutations Enhances Virulence in a Mouse-Adapted H6N6 Influenza A Virus

Cited by 38 publications

References 46 publications

Rapid acquisition of polymorphic virulence markers during adaptation of highly pathogenic avian influenza H5N8 virus in the mouse

Rapid acquisition of polymorphic virulence markers during adaptation of highly pathogenic avian influenza H5N8 virus in the mouse

Host Protein Moloney Leukemia Virus 10 (MOV10) Acts as a Restriction Factor of Influenza A Virus by Inhibiting the Nuclear Import of the Viral Nucleoprotein

Single PA mutation as a high yield determinant of avian influenza vaccines

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